HSPD1 gene polymorphism is associated with an increased risk of ischemic stroke in smokers
Tatiana A. Stetskaya, Ksenia Kobzeva, Sergey M. Zaytsev, Irina Shilenok, Galina V. Komkova, Natalia V. Goryainova, Olga Bushueva
Abstract
Background: Ischemic stroke (IS) is a leading cause of death and disability worldwide. Since the influence of vascular stressors prompts cross-reactivity with microbial and human HSPD1 (HSP60), which results in the degradation of vascular endothelium and intimal infiltration by mononuclear cells, HSP60 is viewed as a key player in the autoimmune theory of atherosclerosis. The aim of the study: The present pilot study investigated whether the tag SNP rs11682567 HSPD1 is associated with the risk of IS. Materials and methods: DNA samples from 1176 unrelated Russian subjects (708 IS patients and 468 healthy controls) were genotyped for tagging SNP rs11682567 in the HSPD1 gene using the MassArray-4 system. A log-additive regression model was used to interpret the associations between genotypes and IS risk. Results: We discovered that smoking, a major environmental endothelial stressor, dramatically modifies the link between rs11682567 and IS, with a relationship only being seen in smokers (risk allele G; OR = 2.11, 95% CI = 1.17-3.82; P = 0.0075). The functional annotation of this SNP revealed that risk allele G of rs11682567 impacts the expression and alternative splicing of genes that regulate brain ischemia-reperfusion injury, reactive oxygen species production, toll-like receptor 4 internalization, and pro-inflammatory properties. Moreover, allele G rs11682567 creates binding sites for transcription factors jointly involved in biological processes encompass neurogenesis, monocyte differentiation, fatty acid metabolism, cell signalling, and apoptosis. Conclusion: Thus, rs11682567 SNP in the HSPD1 gene represents a novel genetic marker of ischemic stroke, whose significance for the pathogenesis of IS is mediated by smoking.